Abstract

Methods and Results In the Physicians' Health Study, a randomized trial of the use of aspirin and β-carotene in 22 071 apparently healthy men, we documented 433 incident cases of PAD during 11 years of follow-up. After we controlled for age and treatment assignment, daily drinkers (≥7 drinks per week) had a relative risk (RR) of PAD of 0.92 (95% confidence interval, 0.72 to 1.17) compared with the reference group (<1 drink per week). After additional control for smoking, however, the RR was 0.68 (0.52 to 0.89). Further control for exercise, diabetes mellitus, and parental history of myocardial infarction revealed an RR of 0.74 (0.57 to 0.97).

Millions of Americans drink alcohol, with most consuming fewer than three alcoholic drinks per day.1 The adverse health effects of chronic drinking of larger amounts, as well as acute alcohol intoxication, are well established.2 In contrast, moderate drinking appears to decrease the risk of myocardial infarction3 and possibly ischemic stroke.4 Although peripheral arterial disease (PAD) shares many pathophysiological features with coronary and cerebral atherosclerosis5 and is an important cause of morbidity in the elderly,6 the relation of moderate drinking to the risk of PAD is uncertain.

Most epidemiological studies of PAD have used a cross-sectional or retrospective design, and the few with alcohol data have noted either no significant78910111213 or only a weak and inconsistent inverse141516 association. Because smoking is an important confounder, inadequate control for this factor might have biased the results of earlier studies. The Physicians' Health Study17 of 22 071 apparently healthy men provided a unique opportunity to examine the association between moderate drinking and risk of PAD during 11 years of follow-up.

Methods

Subjects and Data Collection

The Physicians' Health Study is a randomized, double-blind, placebo-controlled, 2×2 factorial trial of the use of aspirin and β-carotene for the primary prevention of cardiovascular disease and cancer.17 Briefly, informed consent forms and baseline questionnaires were mailed in 1981 through 1984 to all 261 248 US male physicians between 40 and 84 years of age. Approximately half responded, of whom 59 285 were willing to participate. Physicians were excluded if they had a baseline history of myocardial infarction; stroke or transient ischemic attack; cancer (except nonmelanoma skin cancer); current renal or liver disease, peptic ulcer, or gout; or contraindications to or current use of either aspirin or β-carotene. The 33 223 willing and eligible physicians were enrolled in an 18-week “run-in” that resulted in a randomized sample of 22 071. For the present analysis, we further excluded all participants with a history of PAD (n=121).

At baseline, the physicians completed an abbreviated food frequency questionnaire that asked, “How often do you usually consume alcoholic beverages?” The seven response categories (2+/day, daily, 5-6/week, 2-4/week, 1/week, 1-3/month, and never/rare) were interpreted as number of drinks consumed per unit of time. Participants with missing alcohol data (n=191) were excluded, leaving 21 759 men for analysis. In initial analyses, we found virtually identical relative risks (RR) using either nondrinkers (never/rare) or occasional drinkers (1 to 3 drinks per month) as the reference group, so we combined these two categories to form a single reference group (<1 drink per week). Furthermore, to maintain adequate numbers of end points in all analyses, all other participants were categorized as either weekly drinkers (1 to 6 drinks per week) or daily drinkers (≥7 drinks per week). Thus, the level of alcohol intake was divided into three groups.

At baseline, participants also reported their status for several major cardiovascular risk factors, including age, smoking status (never, past, current), number of cigarettes smoked per day (current smokers only), blood cholesterol level of ≥260 mg/dL, use of lipid-lowering medications, systolic and diastolic blood pressure, use of antihypertensive medication, frequency of vigorous exercise, history of diabetes mellitus, and parental history of myocardial infarction before age 60. The 60-month follow-up questionnaire provided more details about participants' smoking history, including age at which participant started smoking, age at which participant stopped smoking, and amount smoked for both current and past smokers. Participants were classified into pack-years of smoking at baseline using baseline data on amount smoked for current smokers and 60-month questionnaire data on amount smoked for past smokers (because information on amount smoked was collected only for current smokers at baseline). Pack-years were defined as the number of years of smoking (using age at which participant started smoking and age at which participant stopped smoking from the 60-month questionnaire) multiplied by the number of cigarettes smoked daily.

Incident PAD events (ie, onset of intermittent claudication or peripheral arterial surgery) were reported on annual questionnaires; nonrespondents were contacted by telephone. Participants were asked, “Over the past 12 months, have you been newly diagnosed as having intermittent claudication? peripheral artery surgery?” Date of diagnosis (month/year) was provided by participants reporting either condition. Only the first report of PAD was considered in the present analysis. Further validation was not undertaken because we have found highly accurate reporting of other cardiovascular end points by this select group of registered US physicians.17 Follow-up through August 1994 was 99.1% complete.

Statistical Analysis

Mean values or proportions of baseline risk factors were computed for the three levels of alcohol consumption. χ2 test was used to test for the association between alcohol intake and smoking. Proportional hazards models were used to compute the RR of PAD for weekly and daily drinkers compared with those consuming <1 drink per week. To address confounding of the alcohol/PAD association by smoking, we used two approaches: (1) multivariate analyses in the entire cohort, with smoking status and cigarette pack-years as covariates; and (2) restriction of the analysis to never-smokers. Multivariate RR values also were adjusted for age, aspirin and β-carotene treatment assignment, exercise, diabetes, and parental history of myocardial infarction. In the primary analyses, we did not adjust for factors affected by alcohol consumption, namely blood pressure18 and hypercholesterolemia,19 because they may not be confounders but rather effects of exposure and therefore should not be controlled.20 The proportional hazards assumption was confirmed through evaluation of interactions of time with alcohol consumption (P=.50). The presence of a linear trend in RR across alcohol categories was tested using an ordinal variable, with values ranging from 1 (<1 drink per week) to 3 (≥7 drinks per week). All RR values are presented with 95% confidence intervals (CI), and all reported P values are two-sided.

Results

Participants drank relatively small amounts of alcohol, with 97% of all men reporting <2 drinks per day, and 88% of daily drinkers reported a usual intake of 1 drink per day. Compared with the reference group, daily drinkers tended to be older, to smoke more, and to have a higher prevalence of hypercholesterolemia and hypertension (Table 1⇓). Drinkers also tended to have a slightly higher prevalence of vigorous exercise and parental history of myocardial infarction and a lower prevalence of diabetes mellitus.

Baseline Risk Factors and Treatment Group According to Level of Alcohol Intake

By August 1994, during 11 years of follow-up, we had documented 433 incident cases of PAD (367 intermittent claudication and 66 PAD surgery). An age-adjusted model showed no apparent association between alcohol intake and risk of PAD (Table 2⇓). When data were also adjusted for smoking, however, we found a statistically significant, inverse association (P for trend=.005). χ2 analysis of alcohol consumption and smoking confirmed a highly significant association between these two behaviors (P=.0001). In a third model, which included three additional covariates (exercise, diabetes, parental history of MI), daily drinkers remained at a decreased risk of PAD (P for trend=.03); daily drinkers were at a 26% lower risk of PAD than those consuming <1 drink per week. Even further adjustment for possible effects of alcohol (ie, hypertension and hypercholesterolemia) did not materially change the inverse relation of alcohol intake with incident PAD (P for trend=.05). Analysis of the risk of intermittent claudication alone revealed a similar inverse association (results not shown); there were too few cases of PAD surgery to allow meaningful analysis for this specific outcome.

Relative Risk of Peripheral Arterial Disease During 11 Years of Follow-up According to Level of Alcohol Intake

To further address concerns about residual confounding by smoking, we next examined the alcohol/PAD association among never-smokers only. Never-smokers represented 50% of this physician cohort, and they experienced 130 incident cases during 11 years of follow-up. In both the age-adjusted and multivariate models, there was a statistically significant, inverse association between moderate drinking and risk of PAD (P for trend=.02 and .04, respectively). Compared with those consuming <1 drink per week, daily drinkers had a multivariate RR of 0.58 (95% CI, 0.24 to 0.99). As previously noted, further adjustment for potential intermediate variables (ie, hypertension and hypercholesterolemia) did not materially change the inverse association (P for trend=.02); the RR for daily drinkers was 0.50 (95% CI, 0.28 to 0.90).

Discussion

In this large prospective cohort study of US male physicians followed for 11 years, alcohol consumption had an inverse association with risk of PAD. As expected, smoking was an important confounder, whereas the inverse alcohol/PAD association was not subject to material confounding by several other independent risk factors for PAD (ie, age, diabetes, exercise, and family history of myocardial infarction). The inverse association persisted even in models that included hypertension and hypercholesterolemia, possible effects of alcohol consumption. Furthermore, the inverse association between moderate drinking and PAD risk was found using either nondrinkers or occasional drinkers as the reference group.

Prior epidemiological data on the alcohol/PAD association are sparse. To our knowledge, there has been only one prospective cohort study on the subject,21 and the authors of this abstract reported that alcohol intake had no significant association with risk of intermittent claudication in men; in a more recent follow-up, alcohol intake was not a risk factor for incident PAD.22 All other epidemiological studies on the alcohol/PAD association are based on either cross-sectional78101213141516 or retrospective case-control911 studies. Most investigators have found no significant association between alcohol use and PAD,78910111213 but a few have noted a weak and inconsistent inverse association.141516 Most prior studies had limited statistical power due to relatively small numbers of PAD cases and may have been further limited by incomplete control for smoking. In contrast, our prospective cohort study had a relatively large number of PAD cases and sufficient numbers of never-smokers to allow adequate control for important confounding by smoking.

There are several plausible mechanisms by which moderate drinking might reduce the risk of PAD. Experimental studies have shown that moderate drinking increases several HDL subfractions,23 and HDL, in turn, has been linked in a few studies with reduced PAD risk.24 Furthermore, moderate drinking is associated with favorable changes in several hemostatic factors,2526 and these factors may also decrease the risk of incident PAD.27 Finally, alcohol-related peripheral vasodilation28 might also contribute to the observed risk reduction. Indeed, a small clinical trial found that ethanol significantly improved peripheral blood flow in patients with intermittent claudication but not in normal control subjects.29 Thus, moderate alcohol consumption may not only inhibit peripheral artery atherosclerosis and decrease thrombosis leading to acute PAD surgery but also reduce ischemia and clinical symptoms from unrecognized peripheral artery stenoses.

One limitation of the present study is the assessment of incident PAD on the basis of onset of intermittent claudication or peripheral arterial surgery. Although we believe that these end points were accurately reported by these registered US physicians—on the basis of their accurate reporting of several other cardiovascular disorders17 —cross-sectional studies have shown that the prevalence of PAD is higher when noninvasive and objective measures for asymptomatic disease are included.5 If alcohol preferentially dilates diseased peripheral arteries,29 our study may not fully distinguish an effect of alcohol on clinical symptoms from the underlying atherosclerosis. The net bias introduced by not including noninvasive measurement techniques in prospective cohort studies is not known and awaits the results of ongoing epidemiological studies, such as the Atherosclerosis Risk in Communities Study.30

Other limitations of our study included the method of alcohol assessment, inability to distinguish drinking patterns, and the select nature of our cohort. As in most other studies, we relied on self-reported levels of alcohol consumption. Other approaches to alcohol assessment are impractical in large cohort studies,31 and we have found that other health professionals provide reliable reports of alcohol use.32 Furthermore, we found a strong, positive association between alcohol intake and HDL cholesterol concentration (P for trend <.0001) in 1535 participants with baseline lipoprotein values,33 a finding that supports the rank-order validity of the alcohol data. With regard to drinking pattern effects (ie, a potentially stronger inverse association among regular, as opposed to binge, drinkers), our inability to adjust for this factor would tend to bias RR toward the null and would not explain our findings. Finally, the healthy volunteer effect,20 strict exclusion criteria (see “Methods”), and enrollment of only US male physicians have each contributed to the highly select nature of our cohort. There is little biological basis, however, for suspecting that the observed relation between moderate drinking and PAD would be materially different in other groups of men. Furthermore, the relative homogeneity and good baseline health of the cohort offer strong evidence to refute claims that the health benefits of moderate drinking are found only among ill populations.34

In summary, this large, prospective cohort study demonstrates that after control for confounding by smoking, moderate alcohol consumption decreases the risk of PAD. This finding is consistent with previously published data that moderate drinking decreases the risk of other atherosclerotic diseases, such as coronary heart disease3 and possibly ischemic stroke.4 The reduced PAD risk of the drinkers was easily overwhelmed by smoking, however, which remains the most important independent predictor of PAD.5 Accordingly, alcohol consumption should not be seen as a behavior that offsets the adverse impact of smoking; clinical practice and health policy efforts should continue to focus on the elimination of smoking to reduce PAD. As for alcohol, the prospect of heavier drinking and its associated problems complicates any policy recommendation that lifelong abstainers begin drinking or that occasional drinkers increase their alcohol consumption.35 Instead, we suggest that interested patients discuss their drinking habit with their healthcare provider, who can help assess the health risks and benefits of any potential behavioral change and, in that setting, provide an individual clinical recommendation.

Acknowledgments

The Physicians' Health Study is supported by research grants HL-26490, HL-34595, CA-34944, CA-40360, and CA-42182 from the National Institutes of Health. Dr Camargo is supported by institutional training grant HL-07575 from the National Heart, Lung, and Blood Institute. The authors are indebted to Marilyn Chown for her assistance with the data analysis.